Dehydration and isomerization of straight-chain-conjugated polyene esters and acids



llmm n Patented Nov. 27, 1951 UNITED STATES PATENT OFFICE.

DEHYDBATION AND ISODIEBIZATION OF STBAIGHT-CHAIN-CONJUGATED POLY- ENE ESTERS AND ACIDS Edgar M. Shanta, Charles D. Robeson, and Henry Kascher, Rochester, N. Y., assignors, by

mesne assignments, to Eastman Kodak Company, Rochester, N. Jersey a corporation of New No Drawing. Application September 9, 1947, Se-

rial No. 773,088. In Great Britain December 19 Claims. 1 This invention relates to improved methods .for the preparation of esters of p-ionylidene acetic acid and the isoprenologs thereof i. e. vitamin A acid esters. The invention further relates to methods for preparing vitamin A in improved HIC CHI Compound H CH:

Compound I d-ionono HIC CHI Compound III Ester oi flionolscetic acid The hydroxy ester, identified above as Compound III, was then dehydrated by distillation under moderate vacuum (e. g. 3 mm. mercury pressure) or by refluxing with an acid for a short time to produce a mixture of compounds consisting only in part of the desired Compound .IV of the following formula:

IC CH:

Compound IV Ester oi fl-lonylideno acetic acid Poor yields of the order of 525% of this desired Compound IV, which is an intermediate in a proposed vitamin A synthesis, were isolated from this mixture and these small yields adversely aiIected both the promotion of the synthesis as well as its economies.

The preparation of a compound alleged to be Compound IV was reported by Karrer, Salomon, Morf, and Walker using a similar procedure. (Helv. Chim. Acta, 1932, 15, 878) and Sobotka, Darby, Click, and Bloch (J. Amer. Chem. Soc. 1945, 67, 403). Heilbron, Jones, and O'Sullivan (J. Chem. Soc. (London) October 1946, 866) reported, however, that the Reformatsky reaction of p-ionone and ethyl bromoacetate, followed by dehydration, was by no means straight forward and that their own investigations provided additional evidence of its complexity. No clearcut explanation of the cause of the low yield 01' Compound IV was, however, made.

There is accordingly a need the art for an improved and certain method of changing the 7 hydroxy ester of Compound III, as indicated by the general formulas, to the intermediate compound, namely Compound IV, which is required for the vitamin A acid ester synthesis.

This invention, therefore, has for one object to provide an improved method for producing esters of B-ionylidene acetic acid. Another ob- :Iect is to provide a method for producing vitamin A acid esters in improved yield. Still another object is to provide a method for producing straight chain-conjugated polyene esters, and acids in improved yield. Another object is to synthesize vitamin A in improved'yield. Other objects will appear hereinafter.

We have discovered that dehydration of the hydroxy ester (Compound III), by the procedures of the prior art described above, produces at least two compounds. We have found that Compound IV is thus formed in relatively small amounts while a major product of the reaction appears from our analysis to be an isomer of Compound IV which may have the following structure:

HIC CH: s

Compound V Compound V as an isomer of Compound IV and as being the principal compound present.capable of undergoing the change herein described, but

'it is understood that our invention does not require that Compound V have the structure assigned above or that it be the only compound present capable of undergoing the reaction hereinafter described.

In accordance with one aspect of our invention we have found that Compound V can be converted in good yield to the desired Compound IV. which is the intermediate compound required in the particular vitamin A synthesis herein described, by a new process which includes contacting Compound V with a catalyst having the property of labilizing conjugated double bonds and particularly one which attracts ionizing protons under conditions which will promote the isomerization of Compound V to Compound IV. This will increase the content of (1,13 unsaturated ester. Preferably this reaction is conducted at reflux temperatureswhile Compound V is dissolved in a solvent, the catalyst being added thereto. The temperature, reaction time, and catalyst must be suitably adjusted for maximum operating efficiency. If a weak catalyst is used, the reaction time must be lengthened and/or the temperature increased for efficient operation. If a strong catalyst, such as oxalyl chloride is used, the reaction may be carried out at room temperature in several hours. Increasing the temperature shortens the time of reaction but too high a temperature promotes decomposition of the reactants. The reaction may be suitably adjusted within a wide range of temperature, and reaction time, c. g., room temperature to reflux temperature, and from about 5 minutes to about one day or more reaction time. The reaction proceeds until an equilibrium is established between the isomers, Compounds IV and V. The two isomers may be separated by appropriate means e. g. by adsorption, distillation, or solvent extraction. By repetition of the isomerization and separation steps, a yield of as high as 70-80% of Compound IV may be obtained from Compound V or other isomers present. Thus our novel process permits the production of an important intermediate in vitamin A synthesis in improved yields.

In accordance with another and very convenient feature of our invention, the dehydration and isomerization steps may be conducted more or less simultaneously. In this process the preferred type of catalyst is introduced into a solution containing Compound III. or a mixture of Compounds III and V. On heating in the presence of the-preferred type of catalyst, the catalyst first acts to dehydrate Compound III to produce Compour" V and then isomerizes Compound V to give Compound IV. Our investigations indicate that some Compound IV may be directly formed from Compound III during the dehydration reaction. The separation of Compound IV from the reaction, alternating with repeated isomerization of Compound V remaining in the re-- action mixture, will give a high yield of the desired Compound IV.

In the foregoing reactions the preferred Reformatsky reaction catalyst is zinc although magnesium may be employed instead.

In the following general formulas in addition to bromine, X represents other halogens such as iodine and chlorine. Fluorine appears to be less suitable for use in the invention. R in the general formulas represents a hydrocarbon radical such as methyl, ethyl, phenyl, benzyl, octyl,

palmityl, stearyl, allyl, etc. It will be understood that R. usually represents the same and only one radical at a time in the series of reactions; however, the reactions will proceed in a similar manner on a mixture of compounds in which R respectively represents different members of the group. Accordingly, as in the specific reactions described above R represents the ethyl group throughout the explanation. However, the broader conception of the invention is also apparent from these general formulas.

The type of solvents in which the Compounds III, IV and V may be dissolved during the dehydration and isomerizing reactions apparently is subject to wide variation so long as they have substantial solvent power for the reactants. Among the preferred solvents are aromatic solvents such as benzene, toluene and xylene. Acetone and carbon tetrachloride are also suitable. Liquids which are sufficiently inert that they will not enter into the reaction may be used as solvents with satisfactory results. Petroleum ether is a mixture of many low-boiling hydrocarbons but is a satisfactory solvent since all the hydrocarbons present are too inert to react with the material undergoing dehydration.

The interconversion of Compounds IV and V may take place upon the shifting of, a hydrogen atom. Where such an interconversion can take place, the system is known as a prototropic system.

The catalyst is believed to act by promoting the ionization of protons. Promoting the mobility of the hydrogen atoms thereby speeds the I reaction to equilibrium conditions. The preferred catalyst is apparently one which has the strongest attraction for the ionizing protons without having at the same time a destructive effect upon the prototropic compounds. In accordance with our invention we have found that iodine, phosphorus oxychloride, oxalyl chloride, phosphorus trichloride, dimethylaniline hydroiodide, para-toluene sulfonic acid, and phosphoric acid, will promote satisfactory isomerization. Sulfuric acid may be employed but it tends to decompose the compounds somewhat and is, therefore, not as satisfactory as the other catalysts. Sodium ethylate in anhydrous ethanol is suitable for isomerizing the isomeric ester (V) but causes destruction of Compound III.

The quantity of the catalyst used may vary over a wide range. We have achieved satisfactory results while using as little as 3 mg. of iodine per gram of ester. Only slightly better yields were obtained when using 80 mg. of phosphorus oxychloride per gram of ester.

In accordance with still another feature of the invention, the isoprenolog of Compound I may be prepared from Compound IV in the following manner. Compound IV is treated with a hydride such as aluminum hydride or lithium aluminum hydride to reduce the ester group to an alcohol group which in turn is oxidized to a ketone by treatment with an aluminum or magnesium alkoxide, such as aluminum isopropoxide, in the presence of acetone, to form the isoprenolog of Compound I which is illustrated in the following formula:

HIC CHa CH: CH:

Compoimd VI aura- 1cc such as oxalyl'chloride or phosphorous oxychlorideand carry out the reaction at-room. or lower temperature. We prefer to allow the reaction to take place over a period or about 4 hours but it minA activity. 5 heat is applied the time may be shortened to as Compound VI may thus be subjected to a Relittle as 15 minutes. The desired isomer, Comtormatsky reaction, in a manner similar to' that pound VIII, may be separated from Compound IX described in connection with the reactions inand the isomerization continued on Compound IX volving' Compound I, to give Compound VII, the until, after alternate isomerization and separation hydroxy ester isoprenolog of Compound III. 7 10 p B high Yield of the desired Compound V111 me CH. is obtained.

CH; CH3 Compounds VIII and IX like Compounds IV and V may be separated from each other by dis- CILCH CH CH CH 5 CHzOOOR tillation, solvent extraction or adsorption. The CH3 H ease of decomposition of the molecule necessitates distillation under reduced pressure. A still of 5 Compound v11 plate efliciency is eflective in making a 70% sepa- Ester oi a-hydro-fi-hydroxy vitamin i ration of Compound IV from Compound V from As in the case of Compound III, its isoprenolos. o g igg g fiig f sggb f g gg g' ggggg g fiz he hydroxy Compound VII, on dehydration by t Compound VIII may be concentrated by distilsubstantially similar procedure gives predomglamon nately an isomeric Compound IX. This may e cata1ytica11y isomerized by similar methods to igfggg gg gfiggg gg fgs g giz bg $33331 yield a mixture, containing the following Coma '5 unsaturated esters (Compounds IV and VIII) gg and the g i ppssiblly g depends on the fact that the former esters are ich are respec W Y ogs more soluble in certain polar solvents such as pmmds IV and aqueous methanol and dimethyl sulfolane than CH! CH CH are the corresponding 11,}? esters. A preparation )3 of mixed isomers (Compounds iv and v) in the ratio of 1:1 dissolved in petroleum ether was shaken with four fresh portions of dimethyl sulfolane. The residue, after evaporation of petroleum ether, contained Compounds IV and V in the ratio of 65:35. Similarly, after 5 extractions Ester Vitamin A of the mixed isomers with 90% aqueous methanol. BIC Cm CH CH the residual concentrate contained the isomers 3 3 a (Compounds IV and V) in the ratio of 3:2. Chromatographic adsorption may be effectively employed to separate the isomeric esters. The CH; adsorption column may be packed with a mild d IX adsorbent, for instance, sodium aluminum silicate in finely divided form. A solution containing Compound IX is analogous to Compound V and Compounds IV and V or Compounds VIII and IX there is a similar question as to its molecular is dissolved in a solvent, for example, petroleum structure. The structure given is consistent with ether, and added to the adsorption column. The our investigation but it may not be entirely cor- Compound V and Compound 1X esters are more rect. In any event, it appears to be an isomer of strongly adsorbed permitting the (1,13 esters to flow Compound VIII which may be converted to Comthrough the column. Residual 11, 3 esters may be pound VIII in accordance with our invention. washed from the column with petroleum ether. The structure shown for Compound IX is given After the adsorption column is free from the s43 for the sake of convenience but it is understood ester, the Compound V and Compound IX esters that our invention applies to any compound demay be eluted from the adsorbent by a solvent, rived from Compound VII during the dehydration for example, benzene and again subjected to the process which is capable of being transformed M isomerizing reaction. according to the invention to give Compound VIII. Table 1 illustrates the relative effectiveness of This compound or compounds may or may not a number of catalysts employed in producing the have the structure of Compound IX. equilibrium mixture from Compound III.

TABLE 1 Reaction Conditions (v) (Iv) Catalyst an... an.

$25 time, hr. 284m 304m 1 1 10 so 1 can 410 1.46 2 1 10 a 4 649 431 1.51 3 p-toluenesulionic acid. 1 10 50 l 618 428 1.44 4 zinc chloride in acetic acid. 1 10 1 662 316 1.10 6 formic acid l 10 100 1 878 374 2.3.5

1 Benzene, except in No. 4.

We have found that the long chain isoprenolog compounds are more easily decomposed and it is. therefore, preferred to employ as catalysts for the isomeriaation reaction the more active catalysts The amount of the desired Compound IV which is present at equilibrium can be determined from the ultraviolet absorption curve of the reaction mixture and the absorption curves of the pure 8 heating. Table 8 shows that too dilute a solution oi the catalyst delays attainment of equilibisomeric compounds. Compound V. for example, has a strong absorption band at 284 m and Compound IV has a similar band at 304 m Thus, rium.

TABLE 3 No Catalyst i gg' fiz: tinie,hr. n ER 2% an m 301 m1.

1 P001; 1 10 so 1 m 2 P001: 1 40 so 1 1.005 g 1;;

- the ratio of extinction coeflicients The examples cited are of ethyl esters but other (Em 284m esters may be used. Table 4 shows the eflect of Fun 304 allyl and phenyl esters compared with ethyl 1am. l) esters TABLE 4 Reaction Conditions (v) av) E28 No. Ester Catalyst m E15 .c .bent. 1&- 1m 1w 8 II nsue 1351:1111. time 784m 304m! 1 1 40 4 041 1a? 1. s2 2 1 40 3 4 569 865 1.55 3 1 40 4 sea 342 1.01

provides a measurement of the amount of Compound IV present. The lower the ratio becomes the higher the percentage of Compound IV is present. A ratio in excess 012 represents a low concentration of 11,13 unsaturated compound,

The value the ratio for the allyl ester (1.32) corresponds to a percentage oi approximately 0 55% of the 11,13 compound in the equilibrium mixture, whereas the value of 1.64 corresponds to a value 01' about 31% afi compound in the equilibwhile a ratio less than 1.7 represents a high conrium mixture.

. TABLE 5 Per esnt g.]Cattacc. 81:1- :31.1 (w) (v) Em I V611 11161 No. Ester Solvent Time Temp. Catalyst ge a 1 2 EH n m n 11111 analysis) 1 78 P00]: 0 0o 10 o 381 1, 01s 2. s7 2 7s P0011 0100 10 4a 389 sec 1.45 3 70 P001; 0.00 10 45 no 070 1.66

4 78 P0 011 0. 0c 10 45 451 731 1. s4 5 v 78 HsP0| 0.09

r0011 0.10 45 422 007 1.58 e V acetone (O5%).-.... 36hr. 55 E1801 0.60 10 45 408 768 1.88 7 V benzene aceticacid l0 40 E1801 0.37 12.5 422 642 1.62

centration of (1,5 compound. This ratio is shown Table 5 indicates that attainment of equilibin the right-hand column 01 Table l.

rium by the use of phosphorous oxychloride and TABLE 2 I benzene requires more than one hour of refluxing according to the procedure which is eflective on hydroxy esters (Compound III). On this table the percentage of Compound IV present in the isomerization mixture is indicated by infra red spectrum measurements as well as by ultra violet absorption measurements. As with the ultra a violet method purified preparations of 11,5 and isomeric ester are used to standardize the analyt- Beaction Conditions (V) (IV) E284 O H. Eii... E804 f cc. solvent lys't' mg time, in- 284 m 304 m 1 Iodine 1 toluene, 10 cc 3 0.5 052 441 1.65 2 P001; 1 ....do 0.2 719 444 1,6 3 .do l benzene, 10cc. 80 l 743 428 1.74 4 do 1 iso ropyl ether, 10 80 l 963 466 2.07 5 ...do 1 car 11 tetrachloride, 10cc 80 1 764 458 1.67 6 .do 1 peltgoleum ether, Skellysolve B, 80 l 648 458 1.42

The concentration 01' reactants used depends principally on the catalyst and on the time 01 ical procedure.

Experiments 2 and 3 in Table 5 show that "rechloride is suillcient to effect an isomerization to the equilibrium point (approximately 50% p esters). Carbon tetra-chloride appeared to be slightly superior to benzene as a solvent because less destruction of esters occurred. Experiment 4 indicates that the addition of 20% of hydroxy ester (Compound III) to isomeric ester was sufflcient tocause isomerization to occur with phosphorous oxychloride and benzene in one hour. Experiments 5, 6, and 7 show the effectiveness of various mineral acid catalysts in eflecting isomerization of isomeric ester.

The above tables illustrate the application of our invention to Compounds III, IV, and V. The following examples illustrate the application of our invention to Compounds VII, VIII, and IX.

for 35% Compound VIII by infra red spectrum and had lf... (848 my) =1045 Example 2.Isomerization of Compound 1;;

Compound IX which is separated in Example 1 by chromatography is isomerized to a mixture of Compounds VIII and IX in the following manner:

0.4 g. of Compound IX ester,

El'f (348 m 1500 was dissolved in cc. of benzene containing 0.025 cc. of phosphorous oxychloride and refluxed 25 minutes. The reaction was worked up by washing with water, drying and evaporation of solvent. The product assayed for 35% Compound VHI b infra red analysis and had izm. u) =1054 Compound IX may be more easily isomerized if Compound VII is present in about the ratio of 40:60 Compound VII to Compound IX.

The examples previously given illustrate the production of straight-chain-conjugated polyene esters in improved yield. Any of the esters may be converted to the corresponding straight-chainconjugated polyene acids by the standard methods, such as alkali saponiflcation or acid hydrolysis.

Compound VIII is vitamin A acid ester. It has about 10% of the vitamin A activity of an equivalent amount of natural vitamin A. It may be saponifled to yield vitamin A acid or it may be reacted with lithium aluminum hydride (LiAlHl) to give vitamin A alcohol.

The synthesis of vitamin A in improved yield by using our invention is illustrated in the following example:

Example 3.-Preparation of vitamin A from fi-ionone (Compound I) Preparation of the ethyl ester of s-ionolacetic acid (Compound III) .--96 g. (0.5 mole) p-ionone, 96 g. (0.575 mole) ethyl bromoacetate, 37.6 g. (0.575 atom) zinc dust, 250 ml. benzene, and a crystal of iodine were heated to refluxing until a reaction commenced. When the spontaneous evolution of heat had ceased the mixture was refluxed 30 min., cooled, shaken with excess 5% hydrochloric acid, and the benzene layer washed successively with water and dilute sodium bicarbonate solution. After drying over sodium sulfate, the benzene was evaporated. and the residue of crude Compound III distilled in a cyclic molecular still to give a purer Compound III as a pale yellow, viscous oil,

E},,,, (231 m =200 (in ethanol) Another preparation had Eu... (23 y) =205 Preparation of the ethyl ester of p-iomrlidene acetic acid (Compound IV) .-CompoundIII (14.8 g.) was dissolved in benzene (106 cc.). 0.5 cc. of POCla dissolved in 42 cc. benzene was added, and the mixture refluxed for one hour. The benzene solution was cooled, passed through 15 g. of sodium aluminum silicate, and washed through with additional benzene (100 cc.). After removal of the solvent in vacuo, the residue was dissolved in 100 cc. of petroleum ether and passed through a column 2 inches in diameter and packed for a length of 20 inches with finely divided sodium aluminum silicate. The column was then washed with 1.8 liters of petroleum ether. The petroleum ether was evaporated from the material which had passed through the column leaving 8 grams of purified ethyl ester of B- ionylidene acetic acid.

The column was eluted with 1.3 liters of acetone to remove the isomeric Compound V from the adsorbent. The acetone was evaporated from the solution to leave 6.5 grams of Compound V. This was dissolved in 35 cc. of'benzene and 0.21 cc. POCls in 30 cc. benzene was added. The mixture was refluxed for six hours after which it was cooled, washed repeatedly with water, then dried by addition of sodium sulfate, filtered, and the solvent evaporated.

The residue, which consisted of 6.4 grams of a mixture of Compounds IV and V, was dissolved in cc. of petroleum ether and passed through an adsorption column as before. After washing with about 600 cc. of petroleum ether, the solvent was evaporated from the material which had passed through the column to yield 3 grams of Compound IV.

The column was eluted with acetone and the acetone evaporated to leave 3.3 grams .of Compound V. This compound was reserved for addition to some Compound V from a fresh batch before further isomerization was attempted.

It will be observed that from 14.8 grams of the ethyl ester of ,B-ionolacetic acid 11 grams of substantially pure compound IV was prepared and sufficient material was left for further isomerization to yield an additional gram of Compound IV. This represents approximately an yield of CompoundIV. All of the Compound V produced is available for isomerization. The only losses in yield are caused by decomposition during refluxing, destruction on the adsorption column, mechanical losses, and a slight quantity of side product produced during the processing operations.

Separation of Compounds IV and V may also be effected by fractional distillation under vacuum or by solvent extraction. In either case the isomer of Compound IV is available for further isomerization in accordance with the method explained above.

Preparation of p-ionylidene eth'anol.4.6 g.

acid was added, and the ether layer washed withwater, dried by the addition of g. of sodium sulfate, and 'tlie solvent evaporated, to give 4.0 g. or product.

E15,. (265 mp) =534 (in ethanol) um bicarbonate, and water. The ether was dried and evaporated to give Compound VI admixed with unreacted p-ionylidene ethanol and other impurities. It was purified by chromatographing, on finely divided sodium aluminum silicate from petroleum ether solution, and had E12,, (345 mp) =99O The semi-carbazone melted at 188-189, and had EFL, (344 my) 1630 Preparation of the ethyl ester of a-hydro-phudrozz vitamin A acid (Compound VII) .3.1 g. 01. Compound VI, 4.2 g. of ethyl bromoacetate, 1.5 g. of zinc dust, ml. of benzene, and 5 mi. of ethyl ether were heated to reflux until a reaction commenced. When the spontaneous evolution ofheat ceased the mixture was refluxed minutes, cooled, shaken with excess 5% hydrochloric acid, and the benzene layer washed successively with water and dilute potassium hydroxide solution. The mixture was dried over sodium sulfate and filtered. The benzene was evaporated under vacuum yielding a residue con sisting of Compound VII. This ester had El; (290 mp)=730 Another preparation had Ell... 9 ms) Preparation of the ethyl ester of vitamin .4. acid (Comp und VIII) .-To 3.8 g. of Compound VII dissolved in 3.4 cc. of benzene, was added 0.21 cc.

, Compounds VIII and its isomer IX. This mixture which had ER... (348 my) =1130 was dissolved in petroleum ether cc.) and chromatographed through a column of sodium aluminum silicate (135 g.). The column was washed with 600 cc. of petroleum ether. The petroleum ether was then evaporated from the material which had run through the column leaving as a residue 1.2 grams of the ethyl ester of vitamin A acid. The material had Another preparation had E};.., (350 mp.)=1080 The column was then eluted with 600 cc. of

benzene-petroleum ether mixture (80:20) to remove Compound IX plus a small amount of Compound VIII which had been held on the ad-- sorbent. The benzene-petroleum ether mixture was evaporated under vacuum to 1.6 grams of Compound IX, the isomer of Compound VIII.

This Compound IX was then mixed with .053 cc.-

of oxalyl chloride in 16 cc. of benzene and allowed to stand in the dark for 8 hours at room temperature. The solution was then passed throu h another column of sodium aluminum silicate (5-10 g.), washed through with additional solvent, and evaporated under vacuum to leave a residue consisting of Compounds VIII and IX. This residue was dissolved in 15 cc. of petroleum ether and separated by chromatographing as described above, yielding an additional 0.5 g. of Compound VIII. The Compound IX plus a small amount of Compound VIII which was retained on the column was eluted with benzene-petroleum ether as described above, the solvent evaporated. and the residue, which consisted of 1 g., was

ready to be run through an isomerization treatment again.

As was the case with separation of Compounds IV and V, distillation under vacuum and solvent extraction could have been used to effect separation of Compounds VIII and IX and Compound IX could have been subjected to another isomerization.

The various catalysts specified in the above isomerizatlons are not the only ones which could have been used. Other catalysts of the type described in this specification would have been satisfactory. Of these catalysts phosphorus oxychloride and oxalyl chloride are satisfactory for use at room temperature or even lower.

Preparation of vitamin A alcohol.0.75 g. oi. Compound VIII was dissolved in 10 ml. of dry ether and 10 ml. of a 0.68 N ethereal solution of lithium aluminum hydride was added over a period of 2 minutes. The solution was agitated for five additional minutes after which 15 ml. of

5% acetic acid was slowly added, the ether layer was washed with water, 5% sodium carbonate solution, and again with water to neutrality.

- After drying of the ether solution over sodium c p-unsaturated polyene compound having the formula H1O CH:

OH: I

wherein n is a whole integer not less than 1 and not greaterthan two and-R is a member of the class consisting of hydrogen and hyccocarbon radicals which comprise substantially complete- 1y dehydrating an a-hydro-p-hydroxy hydrate of said ans-unsaturated polyene compound and thereby forming a mixture of said ass-unsaturated polyene compound and a structural isomer wherein n is a whole integer not less than 1 and not greater than two and R is a member of the class consisting of hydrogen and hydrocarbon radicals which comprises substantially completely dehydrating an a-hydro-p-hydroxy hydrate of said exp-unsaturated polyene compound and thereby forming a-mixture of said cap-unsaturated polyene compound and a structural isomer thereof, converting a substantial amount of said structural isomer present in said dehydrated mixture to said c-unsaturated polyene compound by treating said dehydrated mixture with an ionizing proton attractor selected from the group consisting of acidic materials and iodine, separating said l p-unsaturated polyene compound from said structural isomer, and converting a substantial portion of said structural isomer to said a,fi-unsaturated polyene compound by treating said structural isomer with an ionizing proton attractor selected from the group consist ing of acidic materials and iodine.

3. The process of preparing vitamin A acid ester which comprises dehydrating a-hYdl'O-fihydroxy vitamin Aacid ester and thereby forming a mixture of vitamin A acid ester and a structural isomer thereof, separating said vitamin A acid ester from said structural isomer, and

. isomerizing said structural isomer by treating said isomer with iodine and thereby converting a substantial portion of said structural isomer to said vitamin A acid ester.

4. The process of preparing ,B-ionylidene acetic acid ester which comprises dehydrating an ester of p-ionolacetic acid and thereby forming a mixture of p-ionylidene acetic acid ester and a structural isomer thereof, separating saidp-ionylidene acetic acid ester from said structural isomer, and isomerizing said structural isomer by treating said isomer with iodine and thereby converting a substantial portion of said structural isomer to said fl-ion'ylidene acetic acid ester.

5. The process of preparing in good yield an lap-unsaturated polyene compound having a conjugated double bond system and having the formula HaC CH:

CHI

wherein n is a whole integer not less than 1 and not greater than 2 and R is a member selected from the class consisting of hydrogen and hydrocarbon radicals which comprises dehydrating an a-hydro-p-hydroxy hydrate of said rap-unsaturated polyene compound by dissolving said hyl4 drate in an organic solvent and treating said hydrate with an acidic dehydration catalyst, continuing said treating substantially longer than necessary to effect substantially complete dehydration and thereby forming a, mixture of said mp-unsaturated polyene compound and a structural isomer thereof, separating said mil-unsaturated compound from said structural isomer, and isomerizing said structural isomer by treating said isomer in solution in an organic solvent with an acidic material and thereby converting a substantial portion of said structural isomer to said tap-unsaturated polyene compound.

6. The process of preparing in good yield an a,;8-unsaturated polyene compound having the formula HIC CH:

CH! CH ==CH(B=CH 000R air-unsaturated compound and a structural iso-' mer thereof, said refluxing being continued substantially beyond the time necessary to eiTect substantially complete dehydration until said mixture contains substantially equilibrium proportions of said r p-unsaturated polyene compound and said structural isomer, separating said afiunsaturated polyene compound from said structural isomer, and isomerizing said structural isomer by refluxing an organic solvent solution of said isomer containing an acidic material and thereby converting a substantial portion of said structural isomer to said afi'unsaturated polyene compound.

\ 7. The process of preparing in good yield an c p-unsaturated polyene compound having the formula HzC CH:

CH: CH=CH-I!I=CH 0008 wherein n is a whole integer not less than 1 and not greater than 2 and R is a member selected from the class consisting of hydrogen and hydrocarbon radicals which comprises heating a mixture of an a-hydro-p-hydroxy hydrate of said ,5-unsaturated compound and an acidic material for a time substantially longer than necessary for dehydration alone and thereby forming a mixture of said lap-unsaturated compound and a structural isomer thereof, separating said nap-unsaturated polyene compound from said structural isomer, and isomerizing said structural isomer by heating a mixture of said structural isomer and an acidic material for a time suflicient to convert a substantial portion of said isomer to said e-unsaturated polyene compound, said separating and isomerizing being repeated until a major proportion of said a-hydro-p-hydroxy hydrate is converted to said a,]3 unsaturated polyene compound.

15 8. The process of preparing in good yield an l p-unsaturated polyene compound having the formulaene compound and a structural isomer thereof,

said mixture containing an amount of said 1,5- unsaturated polyene compound substantially in excess of the amount present at the time substantially complete dehydration is effected, and separating said mfl-llIiSfitllldtfid polyene compound from said structural isomer thereof.

9. The process of preparing in good yield an a,p-unsaturated polyene compound having the formula wherein n is a whole integer not less than 1 and not greater than 2 and R is a member of the class consisting of hydrogen and hydrocarbon radicals which comprises treating an a-hydro-fi-hydroxy hydrate of said nap-unsaturated polyene compound with an acidic material, continuing said treating substantially beyond the time necessary to effect substantially complete dehydration of said hydrate and thereby forming a mixture of said c p-unsaturated polyene compound and a structural isomer thereof, separating said structural isomer from said c p-unsaturated polyene compound, mixing the separated structural isomer with an additional amount of said a-hydro-p-hydroxy hydrate, treating the resulting mixture with an acidic material and thereby isomerizing a substantial portion of said separated structural isomer to said lap-unsaturated polyene compound, said treating also converting said hydrate to a mixture of said cap-unsaturated polyene compound and said structural isomer thereof.

10. The process of preparing in good yield an afi-llnSatlll'fltGd polyene compound having the formula H3O CH:

wherein n is a whole integer not less than 1 and not greater than 2 and R is a member of the class consisting of hydrogen and hydrocarbon radicals which comprises dehydrating an a-hydro-p-hydroxy hydrate of said as-unsaturated polyene compound to form a mixture of said "16 a s-unsaturated polyene compound and a structural isomer thereof, converting a substantial portion of said structural isomer in said mixture to said mil-unsaturated polyene compound by isomerizing said structural isomer, said isomerizing being effected by treating said mixture with an acidic material fora substantial time following substantial completion oi dehydration of said hydrate, separating said cap-unsaturated polyene compound from said structural isomer, and con HsC CH:

wherein n is a whole integer not less than land not greater than 2 and R is a member of the class consisting of hydrogen and hydrocarbon radicals which comprises refiuxing a mixture of an acidic material and an organic solvent solution of an a-hydrmp-hydroxy hydrate of said a d-unsaturated polyene compound and continuing said refluxing substantially longer thannecessary to eflect substantially complete dehydration of said hydrate, said refluxing being effective to form a mixture comprising said (as-unsaturated polyene compound and a structural isomer thereof, separating said a s-unsaturated polyene compound from said structural isomer by means of solvent extraction, and isomerizing said structural isomer by refluxing a solution of said isomer with an acidic material and thereby converting a substantial portion of said structural isomer to said mil-unsaturated polyene compound.

12. The process of preparing an intermediate in the manufacture of synthetic vitamin A which comprises dehydrating an ester of p-ionolacetic acid and thereby forming a mixture of p-ionylidene acetic acid ester and a structural isomer thereof, separating said p-ionylidene acetic acid ester from said structural isomer, and isomerizing said structural isomer by treating said isomer with an acidic material and thereby converting a substantial portion of said isomer to said p-ionylidene acetic acid ester.

13. The process of preparing fl-ionylidene acetic acid ester in good yield which comprises treating an ester of p-ionolacetic acid with an acidic material and thereby forming a mixture of ionylidene acetic acid ester and a structural iso-'- mer thereof, said treating being continued substantially longer than necessary to effect substan tially complete dehydration and until said mixture contains substantially equilibrium proportions of said p-ionylidene acetic acid ester and said structural isomer, separating said fl-ionylidene acetic acid ester from said structural isomer, and isomerizing said structural isomer by treating said isomer with an acidic material and thereby converting a substantial portion of said arated structural isomer and thereby forming a new mixture of p-ionylidene acetic acid ester and said structural isomer by treating said separated structural isomer additionally with an acidic material, said separating and isomerizing being repeated until a major amount of said [i-ionolacetic acid ester is converted to said B-ionylidene acetic acid ester.

15. The process of preparing vitamin A acid ester which comprises dehydrating e-hydro-phydroxy vitamin A acid ester and thereby forming a mixture of vitamin A acid ester and a structural isomer thereof, separating said vitamin A acid ester from said structural isomer, and isomerizing said structural isomer by treating said isomer with an acidic material and thereby converting a substantial portion of said structural isomer to said vitamin A acid ester.

16. The process of preparing vitamin A acid ester'which comprises heating a mixture comprising an a-hydro-p-hydroxy vitamin A acid ester and an acidic material and thereby producing a mixture of vitamin A acid ester and a structural isomer thereof, said heating being continued substantially longer than necessary to effect substantially complete dehydration and until said mixture contains substantially equilibrium proportions of said vitamin A acid ester and said structural isomer, separatin said vitamin A acid ester from said structural isomer, and isomerizing said separated structural isomer by heating said separated structural isomer with an acidic material and thereby converting a substantial portion of said structural isomer to said vitamin A acid ester.

17. The process of preparing vitamin A acid ester, in good yield which comprises heating a mixture comprising an acidic material and an organic solvent solution of an a-hydro-p-hydroxy vitamin A acid ester and thereby forming a mixture of vitamin A acid ester and a structural isomer thereof, said heating being continued substantially longer than necessary to effect substantially complete dehydration, separating said vitamin A acid ester from said structural isomer, and isomerizing saidseparated structural isomer and thereby forming a further mixture of said vitamin A acid ester and said structural isomer by heating an organic solvent solution of said separated structural isomer additionally with an acidic material, said separating and isomerizing being repeated until a major amount of said e-hydro-fl-hydroxy vitamin A acid ester is converted to said vitamin A acid ester.

18. The method of producing vitamin A in increased yield which comprises converting ionone to fl-ionolacetic acid ester, dehydrating said p-ionolacetic acid ester and thereby forming a mixture of B-ionylidene acetic acid ester and a structural isomer thereof, separating said fl-ionylidene acetic acid ester from said structural isomer, isomerizing said structural isomer by treating an organic solvent solution of said 18 structural isomer with an acidic material for a substantial time and thereby forming an addi-, tional amount of said fl-ionylidene acetic acid ester, reducing said p-ionylidene acetic acid ester to ,s-ionylidene ethanol, oxidizing said p-ionylidene ethanol to a ketone of the formula H3O CH:

CH: CH:

converting said ketone to a-hydro-s-hydroxy vitamin A acid ester, dehydrating said a-hydros-hydroxy vitamin A acid ester and thereby isomer, isomerizing the last said structural isomer following said separating by treating an organic solvent solution of the last said structural isomer with an acidic material for a substantial time and thereby forming an additional amount of said vitamin A acid ester, and reducing said vitamin A acid ester to vitamin A.

19. The process of preparing vitamin A in improved yield which comprises converting p-ionone to s-ionolacetic acid ester, treating said s-ionolacetic acid ester with an acidic material and thereby producing a mixture of p-ionylidene acetic acid ester and a structural isomer thereof, said treating being continued until said mixture comprises substantially equilibrium proportions of said fl-ionylidene acetic acid ester and said structural isomer thereof, separating said structural isomer from said fi-ionylidene acetic acid ester, isomerizing said separated structural isomer by treating said isomer additionally with an acidic material and thereby converting a substantial portion of said structural isomer to said p-ionylidene acetic acid ester, said separating and isomerizing being repeated until a major proportion of said fl-ionolacetic acid ester is converted to said ,fi-ionylidene acetic acid ester, reducing said fi-ionylidene acetic acid ester to B-ionylidene ethanol, oxidizing said p-ionylidene ethanol to a ketone of the formula I acidic material and thereby producing a mixture comprising vitamin A acid ester and a struc ural isomer of said vitamin A acid ester, said treat ing with said acidic material being continued until the last said mixture comprises substantially equilibrium proportions of said vitamin A acid ester and said structural isomer of said vitamin A acid'ester, separating said last-named structural isomer from said vitamin A acid ester, isomerizing said separated structural isomer of said vitamin A acid ester by treating it additionally with an acidic material and thereby converting a substantial portion of said structural isomer of vitamin A acid ester to said vitamin A acid ester, said separating and isomerizin-g being repeated until a major proportion of said a-hydro-p-hydroxy vitamin A acid ester is con- 19 verted to said vitamin A acid ester, and reducing said vitamin A acid ester to vitamin A.

EDGAR M. SHANTZ. CHARLES D. ROBESON. HENRY M. KASCHER.

REFERENCES crmn The following references are of record in the file of this patent:

UNITED STATES PAWS 20 0mm mmmrcms Karrer et al., Helv. Chim. Acta. vol. 29, 704-11 (1946).

Young et 0.1., Jour. Am. Chem. Soc., vol. 69, 2042-6 (1947).

Van Dorp et 0.1., Rec. Trav. Chim., vol. 65. 338-6 (1946).

Isler et al., Experimentia, vol. 2, page 31 (1946).

Miles et a1., Jour. Am. Chem. 800., vol. 69, 2247-8 (1947), rec'd August 26, 1947. 

1. THE PROCESS OF PREPARING IN GOOD YIELD AN A,B-UNSATURATED POLYENE COMPOUND HAVING THE FORMULA
 19. THE PROCESS OF PREPARING VITAMIN A IN IMPROVED YIELD WHICH COMPRISES CONVERTING B-IONONE TO B-IONALACETIC ACID ESTER, TREATING SAID B-IONOLACETIC ACID ESTER WITH AN ACIDIC MATERIAL AND THEREBY PRODUCING A MIXTURE OF B-IONYLIDENE ACETIC ACID ESTER AND A STRUCTURAL ISOMER THEREOF, SAID TREATING BEING CONTINUED UNTIL SAID MIXTURE COMPRISES SUBSTANTIALLY EQUILIBRIUM PROPORTIONS OF SAID B-IONYLIDENE ACETIC ACID ESTER AND SAID STRUCTURAL ISOMER THEREOF, SEPARATING SAID STRUCTURAL ISOMER FROM SAID B-IONYLIDENE ACETIC ACID ESTER, ISOMERIZING SAID SEPARATED STRUCTURAL ISOMER BY TREATING SAID ISOMER ADDITIONALLY WITH AN ACIDIC MATERIAL AND THEREBY CONVERTING A SUBSTANTIAL PORTION OF SAID STRUCTURAL ISOMER TO SAID B-IONYLIDENE ACETIC ACID ESTER, SAID SEPARATING AND ISOMERIZING BEING REPEATED UNTIL A MAJOR PROPORTION OF SAID B-IONOLACETIC ACID ESTER IS CONVERTED TO SAID B-IONYLIDENE ACETIC ACID ESTER, REDUCING SAID B-IONYLIDENE ACETIC ACID ESTER TO B-IONYLIDENE ETHANOL, OXIDIZING SAID B-IONYLIDENE ETHANOL TO A KETONE OF THE FORMULA 